Schizophrenia is a debilitating mental disorder affecting up to 1% of the human population in the United States that involves altered perceptions of reality, cognitive dysfunction, and progressive withdrawal from reality. The development of better antipsychotic medications remains a high priority for research, since current medications are only partially effective and all have serious side effects. The research outlined in this proposal uses a mouse model to address questions about how cellular mechanisms of brain function are altered that may contribute to human schizophrenic symptoms. A better understanding of these cellular mechanisms can be ultimately translated into the development of more effective medications for the treatment of the disorder. Much current research continues to focus on the role of the brain transmitter, dopamine, since alterations in dopamine function are known to contribute to the schizophrenic phenotype. A well-established feature of the disease is a disruption of prefrontal cortical function, and especially working memory. It is known that optimal dopamine function is critical for normal working memory function in the prefrontal cortex, but the mechanisms by which dopamine exerts its actions are poorly understood. Since working memory function is correlated with rhythmic activity in the prefrontal cortex, I propose to test the hypothesis that dopamine regulates working memory by altering rhythmic properties in prefrontal cortical neurons. Specifically, the studies will determine how prefrontal cortical neurons respond to rhythmic stimulation throughout the range of biologically relevant frequencies (ie. frequency-dependent or resonant properties) and how these responses are modified by dopamine. A mechanistic understanding of how dopamine regulates rhythmic activity critical for working memory function in the prefrontal cortex would represent an important step towards further understanding the schizophrenic phenotype. The role of dopamine in the context of recent findings describing roles for other brain neurotransmitters should facilitate the development of more effective antipsychotic medications that exploit the interactions between these brain transmitter systems. PUBLIC HEALTH RELEVANCE: Schizophrenia symptoms include cognitive deficits that implicate the human prefrontal cortex. This project will study the cellular mechanisms by which the neurotransmitter, dopamine, regulates rhythmic activity in the prefrontal cortex, lending insight into the schizophrenic phenotype.